CPG Management of Venous Tromboemlism

8/14/2019 CPG Management of Venous Tromboemlism

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venous thromboembolism


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Statement of Intent

These guidelines are meant to be a guide for clinical practice, based on the bestavailable evidence at the time of development. Adherence to these guidelinesmay not necessarily ensure the best outcome in every case. Every health careprovider is responsible for the management options available locally.

Review of the Guidelines

These guidelines were issued in July 2003 and will be reviewed in July 2005 orsooner if new evidence becomes available.

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Foreword

Venous thromboembolism covers a spectrum of disorders characterized bythrombosis in the venous circulation with its often fatal sequelae. It is a disorder

which is seen across a spectrum of medical and surgical disciplines. Like manydisorders which crosses specialties, it often gets neglected with noparticular specialty claiming ownership. It is therefore pertinent that a multidisciplinary effort be made to guide doctors on various aspects of VTE. Thedisparate figures on incidence and prevalence of VTE between and withinspecialties do not make matters any easier. What is worrisome is that withoutproper guidelines, patients may be under diagnosed and avoidable death notprevented.

In 1999 the Academy of Medicine , College of Surgeons and Ministry of Healthreleased a Consensus on Prophylaxis of Venous Thromboembolism. Two yearslater, the National Heart Association of Malaysia proposed to theAcademy of Medicine that an updated version of the Consensus to includediagnostics and therapeutics aspects be authored. Following approval by theAcademy, a committee comprising of specialists from 13 different specialtieswas formed. All members from the 1999 Consensus committee were invited.

After almost 18 months of endeavour, the Guideline is now ready forcirculation

In view of the scope to be covered .it is inevitable that this current Guideline issomewhat lengthy. It should however be of benefit to a spectrum of specialties.Every effort is made to ensure that references quoted are contemporary andlevels of evidence are highlighted close to the text in question. This is also one of the first (if not the first) Guideline which discusses the economics of disease

management.. It is hoped that other Guidelines will follow suit.

It is our sincere hope that this Guideline will be of use to doctors in preventing andtreating VTE. We pray to the Almighty that we will be successful in putting thelatest available knowledge He has bestowed on us for the betterment of ourpatients.

Prof. Abdul Rashid Abdul Rahman

Chairman VTE CPG Committee

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CommitteesClinical Practice Guidelines Development Group

Chairman : Prof. Rashid Abdul RahmanWriters : Dr Myint Tun

Dr Jameela SatharAssoc. Prof. Yahaya HassanAssoc. Prof. VijeyasingamDr V. PurushothamanAssoc. Prof. BJ AbdullahAssoc. Prof. M.A. Jamil

Dr Tai Li LingDr Tan Kay SinDr Ravindran Jegasothy

Reviewers : Prof. Raymond Azman AliDr Khoo Kah LinAssoc Prof. Roslan HarunDr. Zulkharnain Ismail

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Guideline Development and Objectives

Guideline Development

Venous thromboembolism covers a spectrum of disorders characterized bythrombosis in the venous circulation with its often fatal sequelae. It is a disorderwhich is seen across a spectrum of medical and surgical disciplines. Like manydisorders which crosses specialties, it often gets neglected with no particularspecialty claiming ownership. It is therefore pertinent that a multi disciplinaryeffort be made to guide doctors on various aspects of VTE.

Objectives

The main objective is to guide practitioners on the various aspects of VTEprophylaxis and management incorporating the latest scientific evidence.Diagnostic aspects are also covered in view of the concern that VTE is not onlyunder treated but also under diagnosed in Malaysia.

Clinical Question

The clinical questions addressed in this guideline are:- When and whom VTE prophylaxis should be adopted.

- How to optimize the diagnosis of VTE with currently availablemethods.

- What are the available options in managing VTE and its sequelae.

- Pharmacoeconomics of prevention and treatment of VTE.

Target Population

This guideline are to be applied to patients who are at risk or have developedVTE.

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Target Group

The target group will be mainly doctors working in hospitals, where the majorityof VTE occurs. It will also be of use to general practitioners particularly thoseinvolved with continuing care of patients once they are discharged from thehospitals. Like most CPGs it is meant to guide doctors in making decisions basedon the latest available evidence. It should be used to assist and not replaceclinical judgment and decision making.

GRADING RECOMMENDATIONS

A Based on evidence from one or more randomized clinical trials and/ormeta-analyses

B Based on evidence from non-randomise clinical trials or observationalstudies. These may include subgroups analyses from randomized clinicaltrials.

C Based on expert committee reports and/or clinical experience of respected

authorities. Absence of directly applicable clinical studies of goodquality.

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TABLE OF CONTENTS

1. EPIDEMIOLOGY

1.1 Introduction1.2 Pathogenesis and Natural History of VTE1.2.1 Epidemiology of post-operative DVT in general surgical,

gynaecological and orthopaedic patients in Asianstudies.

1.2.2 Epidemiology of venous thromboembolism in medicalpatients.

1.2.3 Epidemiology of venous thromboembolism in critically ill

patients.1.2.4 Epidemiology of post stroke venous thromboembolism.

2. CLINICAL DIAGNOSIS

2.1 Clinical diagnosis of VTE2.2 Diagnostic approaches for veno-thromboembolic disease

2.2.1 First episode of DVT

2.2.2 Suspected pulmonary embolism2.2.3 Detection of recurrent VTE

3. PROPHYLAXIS

3.1 Introduction3.2 Methods of prophylaxis for moderate and high risk groups3.3 Duration of prophylaxis

3.4 Special considerations3.5 Obstetrics and Gynaecology

4. TREATMENT

4.1 Introduction4.2 Initial treatment of VTE

4.2.1 Heparin regimens

4.2.2 Low Molecular Weight Heparins4.2.3 Adjunct therapy

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4.2.4 Thrombolysis4.2.5 Pulmonary embolectomy4.2.6 Thrombolysis and venous thrombolectomy4.2.7 Endovascular stents

4.3 Maintenance treatment of VTE4.4 Venous thromboembolism in patient undergoing surgery/

anaesthesia4.5 VTE in pregnancy4.6 Recommendations for anticoagulation for established VTE in

stroke patients4.7 Pharmacoeconomics of venous thromboembolism

5. COMPLICATIONS AND SEQUELAE IF VTE

5.1 Antithrombotic therapy and regional anaesthesia5.2 Interior vena caval filters5.3 Pulmonary embolectomy5.4 Catheter transvenous extraction or fragmentation of pulmo-

nary emboli5.5 Venous thrombectomy5.6 Chronic venous insufficiency

APPENDIXES

1 Imaging of pulmonary embolism2 Clinically significant warfarin drug interactions3 Potential warfarin interactions with dietary supplements4 Key elements of patient education regarding warfarin

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1.1 INTRODUCTION

There is an increasing incidence of venous thromboembolism (VTE) among theAsian population partly because of greater awareness among doctors andpatients themselves. The incidence of VTE varies in different parts of the worldfor reasons not completely understood. The worldwide incidence exceeds 1 per1000. 1,2

Postoperative deep vein thrombosis (DVT) is believed to be rare in Asians. Studiesin the region however, have shown that the incidence ranges from 2.2 62.5% 3

(refer to Table 1).

Pulmonary embolism (PE) is the cause of death in 0.9% of all hospital admissionsand remains the main cause of maternal death in the United Kingdom. 4 InMalaysia, PE is the third cause of maternal mortality according to the report onConfidential Enquiries into Maternal Deaths from 1991 to 1996. 5

1.2 PATHOGENESIS AND NATURAL HISTORY OF VTE

Venous thrombosis results from an imbalance between thrombogenic factors andprotective mechanisms. Thrombogenic factors include activation or destructionof vascular endothelium, activation of platelets or blood coagulation, inhibition of fibrinolysis and stasis.

Silent DVT usually starts in the venous sinuses of the calf muscles and in 20% itextends to the proximal veins. 6These patients are at risk of PE.Thromboembolism in hospital patients depends not only on the underlying diseaseand trauma of surgery but also on patient-related variables (Table 2).

1Chapter 1 : Epidemiology


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Table 1: Incidence of post-operative deep vein thrombosis in Asianpatients

Gen. Surg: General surgical patients


1.2.1 Epidemiology of post-operative DVT in general surgical,gynaecological and orthopaedic patients in Asian studies.

In general surgical patients, Western studies report an incidence ranging from33% to 35%. 8-10 Asian studies revealed a lower incidence ranging from 2.2% to15.3% 11-14 in general surgical patients and 2.4% in gynaecological patients. 15

In orthopaedic patients after hip and knee surgery, the incidence ranges from 4%to 62.5%. 3,16-19 This is in contrast to Western figures ranging from 45-84% 20,21

Author and Country

Cunningham and Yong(Malaysia)

Nandi et al(Hong Kong)

Inada et al(Japan)

Tun et al(Malaysia)

Chumnijarakij andPoshyachinda,(Thailand)

Mok et al(Hong Kong)

Kim and suh(S. Korea)

Atichartakarn et al(Thailand)

Mitra, Khoo and Ngan(Singapore)

Dhillon et al(Malaysia)

Year

1974

1980

1983

2001

1975

1979

1988

1988

1989

1996

PostoperativeDVT incidence

percentage

12.0

2.6

15.3

2.2

2.4

53.3

10.0

4.0

9.7

62.5

Type of patients studied

& No.

Gen. Surg6 8

Gen. Surg1 5 0

Gen. Surg2 5 6

Gen. Surg4 5

Gynaecology1 6 9

Orthopaedic5 3

Orthopaedic1 4 6

Orthopaedic5 0

Orthopaedic7 2

Orthopaedic8 8

Method of investigation

125I fibrinogen

125I fibrinogen

125I fibrinogen

Duplex Ultrasound andVenography

125I fibrinogen

Ascending venography






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Table 2: Risk factors for Thromboembolism from ThromboembolicRisk Factors (THRIFT) Consensus Group, 1992 7

1.2.2 Epidemiology of Venous Thromboembolism in medical patients.In contrast to surgical patients, VTE has been less well studied in hospitalisedmedical patients. In chronically ill patients such as congestive cardiac failure,chronic obstructive airway disease or infections, the DVT rate in the absence of prophylaxis has been reported to be approximately 16%. 22

Patient factors

Age

Obesity

Varicose veins

Immobility (bed rest over 4 days)

Pregnancy

Puerperium

High dose oestrogen therapy

Previous DVT or PE

Thrombophilia

Deficiency of antithrombin,Protein C or Protein S

Antiphopholipid antibody or

Lupus anticoagulant

Disease or surgical procedure

Trauma or surgery especially of pelvis, hip,lower limb

Malignancy, especially pelvic, metastatic

Heart failure

Recent myocardial infarction

Paralysis of lower limbs

Infection

Inflammatory bowel disease

Nephrotic syndrome

Polycythaemia

Paraproteinaemia

Paroxysmal noctural haemoglobinuria

Bechcets disease, homocystinaemia



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1.2.3 Epidemiology of venous thromboembolism in critically ill patients.Cross-sectional studies of medical and surgical intensive care unit patients haveshown that approximately 10% 23,24 has proximal DVT on admission to the ICU.The prevalence of DVT in patients in the medical-surgical ICU is 25-32%. 25-28

Patients with multi system or major trauma have a risk for DVT that exceeds50% 29 and fatal PE occurs in approximately 0.4 to 2.0%. Among trauma subgroups,high rates of DVT were seen in patients with lower extremity (69%) and spine(62%) fractures and in patients with major head injuries (54%).

1.2.4 Epidemiology of post-stroke deep venous thrombosisMost of the available epidemiological data have been collected in Western. Therewere also different diagnostic modalities used in the studies.

The incidence of DVT after ischaemic stroke ranged from 11-53%. 31-32,34-36,39,40

Significant risk factors were time interval without prophylaxis (ie time from stroketo admission), lower active movement scores for limb movement and artrialfibrillation. 30,31 Prevalence data ranged from 6.3% to 33%. The lowerprevalence comes from 2 Asian studies and may reflect the lower prevalence of DVT in Asians. 34,38

Table 3: Prevalence on DVT in ICU

Author

Cade JF 26

Fraisse 27

Hirsh 25

Marik 28

Year

1982

2000

1995

1997

DVT prevalence, %

29%

28%

32%

25%

Sample size

119 medical-surgicalICU pts

85 COPD pts onmechanical ventilation

Medical ICU pts

102 medical and

surgical ICU pts

Method of investigation125 I fibrinogen

Contrast venography

Doppler ultrasound

Doppler ultrasound



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A summary of the related studies is presented below.

Table 4: Prevalence and incidence of deep vein thrombosis in strokepatients

Author and Country

S.Tongiputn,N.Kunanusont et. al. 38

(Thailand)

P.Noel, F.Gregoire et. al. 30

(Belgium)

G.Pambianco, T.Orchard,P.Landau 31 (USA)

W.J.Oczkowski et. al. 32

(Canada)

ER Sioson et al 33 (USA)

S.C.Tso 34 (Hong Kong)

Miyamota AT, Miller LS 35

(USA)

C.Warlow, D.Ogston,AS Douglas 39 (Scotland)

F B Gibberd et. al. 40

(England)

Cope et. al. 35 (England)

Year

1999

1991

1995

1992

1988

1980

1980

1976

1976

1973

DVT incidenceprevalence*

percentage(%)

6.3*

10.4*

2 1

1 1

3 3 *

1 7

2 9

5 3

5 0

3 3

Sample size

1 1 1

5 3 9

5 0 8

1 5 0

1 0 5

3 5

1 5 0

7 6

2 6

1 5 0

Method of investigation

Ultrasound

Venography

Ultrasound

ImpedancePlethysmography

ImpedancePlethysmography

125 I-fibrinogen

125 I-fibrinogen

125 I-fibrinogen

125 I-fibrinogen

Ascending

venography



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REFERENCES:1. Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T, A prospective study of the incidence

of deep vein thrombosis within a defined urban population. J Intern Med. 1992; 232: 155-160.

2. Anderson FA, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, ForrierA, Dalen JE. A population based perspective of the hospital incidence and case fatality ratesof deep vein thrombosis and pulmonary embolism. The Worcester DVT study. Arch InternMed. 1991; 151: 933-938.

3. Dhillon KS, Askander A, Doraisamy S. Postoperative deep vein thrombosis in Asian patientsis not a rarity. J Bone Joint Surg (Br) 1996; 78-B: 427-430

4. Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are wedetecting enough deep vein thrombosis? J R Soc Med 1989; 82: 203-205.

5. Ravindran J., Mathews A. Maternal mortality in Malaysia 1991-1992: the paradox of increased rates. J Obstet Gynaecol. 1996; 16 (2): 86-88.

6. Kakkar VV, Corrigan TP, Fossard DP et al: Prevention of fatal postoperative pulmonaryembolism by low doses of heparin. An international multicentre trial. Lancet 1975; 2:45-54.

7. Geerts WH, Heit JA. Prevention of venous thromboembolism. Chest 2001; 119:132S-175S8. Flanc C, Kakkar VV and Clark MB. Detection of venous thrombosis of the legs using 125 I-

labelled fibrinogen. Br J Surg 1968; 55: 542-547.9. Kakkar VV, Howe CT, Nicolaides AN, Renny JTG and Clark MB. Deep vein thrombosis of

the legs is there a high risk group? Am J Surg 1970; 120: 527-530.10. Borow M, Goldson H. Postoperative venous thrombosis: evaluation of five methods of

treatment. Am J Surg 1981; 141: 245-251.11. Cunningham IGE, Yong NK. The incidence of post-operative deep vein thrombosis in Malay-

sia. Br J Surg 1974; 61:482-483.

12. Nandi P, Wong KP, Wei WI, Ngan H, Ong GB. Incidence of deep vein thrombosis in HongKong Chinese. Br J Surg 1980; 67:251-253.

13. Inada K, Shirai N, Hayashi M, Matsumoto K, Hirose M. Postoperative deep vein thrombosisin Japan: incidence and prophylaxis.Am J Surg 1983;145:775-779.

14. Tun M, Shuaib IL, Muhamad M, Mat Sain AH & Ressang AS. Incidence of post-operativedeep vein thrombosis in general surgical patients of Hospital Universiti Sains Malaysia.Malaysian J Med Sciences 2001; 8: 67.

15. Chumnijarakij T, Poshyachinda V. Postoperative thrombosis in Thai women. Lancet 1975; 1:1357-1358.

16. Mok CK, Hoaglund FT, Rogoff SM, Chow SP, Ma A, Yau ACMC. The incidence of deep

vein thrombosis in Hong Kong Chinese after hip surgery for fracture of the proximal femur. BrJ Surg 1979; 66: 640-642.

17. Kim YH, Suh JS. Low incidence of deep vein thrombosis after cementless total hip replacement.J Bone Joint Surg (Am) 1988; 70-A: 878-882.

18. Atichartakarn V, Pathepchotiwong K, Keorochana S, Eurvilaichit C. Deep vein thrombosisafter hip surgery among Thai. Arch Intern Med 1988; 148: 1349-1353.

19. Mitra AK, Khoo TK and Ngan CC. Deep vein thrombosis following hip surgery for fractureof the proximal femur. Singapore Med J 1989; 30: 530-534.

20. Stulberg BN, Insall JN, Williams GW, Ghelman B. Deep vein thrombosis following total kneereplacement: an analysis of six hundred and thirty-eight arthroplasties. J Bone Joint Surg(Am)1984;66-A:194-201.

21. Hull RD, Raskob GE. Prophylaxis of venous thromboembolic disease following hip and kneesurgery. J Bone Joint Surg(Am) 1986;68-A:146-150.



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22. Hirsh, J., Warketin, T.E., Shaughnessy, S.G., Anand, S.S., Halperin, J.L., Raschke, R., Granger,C., Ohman, E.M., and Dalen, J.E., (2001), Heparin and Low Molecular Weight Heparin Mechanisms of Action, Pharmacokietics, Dosing, Monitoring, Efficacy, and Safety, CHEST2001, p.119:64S-94S.

23. Schonhofer B, Kohler D. Prevalence of deep-vein thrombosis of the leg in patients with acuteexacerbation of chronic obstructive pulmonary disease. Respiration. 1998;65:173-177

24. Harris LM, Curl GR, Booth FV. Screening for asymptomatic deep vein thrombosis in surgicalintensive care patients. J Vasc Surg. 1997;26:764-769.

25. Hirsh DR, Ingenito EP, Goldhaber SZ: Prevalence of deep venous thrombosis among patientsin medical intensive care. JAMA 1995; 274: 335337

26. Cade JF. High risk of the critically ill for VTE. Crit Care med 1982; 10:448-45027. Fraisse F, Holzapfel L, Couland J-M. Nadroparin in the prevention of deep vein thrombosis

in acute decompensated COPD. Am J Respir Crit Care Med 2000; 161:1109-111428. Marik PE, Andrews L, Maini B. The incidence of deep venous thrombosis in ICU patients.

Chest. 1997;111:661-664.29. Geerts WH, Code KI, Jay RM. A prospective study of VTE after major trauma. N Engl J

Med 1994 331:1601-160630. Noel P, Gregoire F, Capon A, Lehert P. Atrial Fibrillation as a risk factor for Deep Venous

Thrombosis and pulmonary emboli in stroke patients. Stroke ;22:6;760-76231. Pambianco G et al. Deep Vein Thrombosis: Prevention in Stroke Patients during

Rehabilitation. Arch Phys Med Rehabil :76;324-33032. Oczkowski WJ et. al. Venous Thromboembolism in patients undergoing rehabilitation for

stroke. Arch Phys Med Rehabil :73;712-71533. ER Sioson et.al. Occult proximal deep vein thrombosis:Its prevalence among patients admitted

to a rehabilitation hospital Arch Phys Med Rehabil :69;183-185

34. Tso SC. Deep vein thrombosis after stroke in Chinese. Aust NZ J Med 1980;10:513-51435. Cope C, Reyes T, Skversky N Phlebographic analysis of the incidence of thrombosis inhemiplegia. Radiology 1973;109:581-4

36. Miyamota et. al. Prevention by early heparinization of venous thrombosis detected by I-125fibrinogen leg scans Arch. Phys. Med Rehabil 1980;61:584-587

37. Brandstater ME et. al. Venous thromboembolism in stroke: literature review and implicationsfor clinical practice. Arch Phys Med Rehabil 1992;73:S379-391

38. S.Tongiputn, S.Kunanosont et. al. (1999) Lower extremity deep vein thrombosis among Thaipatients with stroke. Neurol J South East Asia ;4:13-18

39. Warlow C., Ogston D., Douglas AS(1976) Deep venous thrombosis of the legs after stroke.

British Medical Journal , 1:1178-118340. Gibberd FB, Gould SR, Marks P.(1976) Incidence of deep vein thrombosis and leg oedema in

patients with stroke. Journal of Neurol, Neurosurg. Psychiatry 1976:39;1222-1225



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2.1 CLINICAL DIAGNOSIS OF VTE

Review of the literature between 1966 and 1997 performed by Anand 1

demonstrated that the sensitivity of clinical assessment in diagnosis of DVT rangedfrom 60% to 96% while the specificity ranged from 20% to 72%. To diagnoseDVT, clinical assessment must be supplemented. This is especially true inpregnancy because leg swelling and pain are physiological consequences of pregnancy.

Clinical models are available for the prediction of both DVT and PE(Tables 1 & 2)

Clinical Assessment of DVT in Lower LimbTable 1: Clinical Model for Predicting Pretest Probability of Lower

Limb DVT 2

In patients with symptoms in both legs, the more symptomatic leg is used.

Clinical Assessment of DVT in Upper LimbIn the upper limbs, DVT is an increasingly common problem but the clinicaldiagnosis is non-specific with less than 50% being symptomatic. 3

If Present

Risk FactorsActive cancer (treatment ongoing or within previous 6 months or palliative)Paralysis, paresis or recent immobilization of lower extremitiesRecently bedridden more than 3 days or major surgery within 4 weeksClinical Signs

Localized tenderness along the distribution of the deep venous systemEntire leg swollenCalf swelling 3 cm > asymptomatic side (measured 10 cm below tibial tuberosity)Pitting odema confined to symptomatic legCollateral superficial veins (non-varicose)Alternative diagnosis as likely or greater than that of DVT

Score

111

11111

- 2

High Probability Moderate Probability Low Probability

>3 1 - 2


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Clinical Assessment of Pulmonary Embolism (PE)Table 2: Clinical Model for Predicting Pretest Probability for

Suspected PE 4

Classical symptoms and signs of acute PE apart from sudden death notmentioned in the table include chest pain, dyspnoea, hypotension andelevated jugular venous pressure. Routine investigations should includechest x-ray (pruning of pulmonary vessels, atelectasis, wedge shapedopacity). ECG (tachycardia, right heart strain, S1, Q3, T3 pattern) and

echocardiogram show right heart strain. Arterial blood gases will showhypoxia.

Symptoms & Signs

Clinical signs & symptoms of DVT (minimum of leg swelling & pain withpalpation of deep vein)An alternative diagnosis is less likely than PEHeart rate greater than 100 beats/minImmobilization or surgery in previous 4 weeksPrevious DVT/PEHaemoptysisMalignancy (at treatment, treated in the last 6 months or palliative)

Score

3. 0

3. 01. 51. 51. 51. 01. 0

High Probability Moderate Probability Low Probability>6 2 - 6


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2.2 DIAGNOSTIC APPROACH FORVENO-THROMBOEMBOLIC DISEASE

Numerous algorithms have been suggested for the diagnosis of VTE. These willdepend on the availability of imaging facilities, the studies used as reference as

well as the philosophy of the referring doctor. It must be recognised that theclinical probability of VTE must be a part of any of these algorithms.

2.2.1 First episode of DVTFigure 1 is a suggested protocol for diagnosis of the first episode of symptomaticacute DVT. The tests along with the advantages, disadvantages and commentsare presented in Appendix I.

Clinical assessment is pivotal in providing safe management when radiographicimaging is not routinely available. Those with moderate or high clinicalprobability should receive unfractionated or low-molecular weight heparin in dosesdesigned to treat acute DVT 5 with imaging which may be delayed until the nextday if it is not immediately available. However, for those with low clinicalprobability, imaging can be delayed 12 to 24 hours without anticoagulantcoverage. 5

Patients should first undergo Duplex ultrasound (US) with manual compressionsince it has proved to be highly sensitive and specific in symptomatic acuteproximal DVT. A positive test is sufficiently predictive that treatment should becontinued or initiated. Approximately 10% to 20% of patients have DVTconfined to the calf veins where the sensitivity and specificity of the US aredefinitely less. However, about 20% to 30% of the isolated distal DVT will haveproximal propagation. Serial ultrasound testing has evolved to solve this problem.Patients with negative serial US have less than 1% risk of developingsymptomatic DVT or PE in a 3-month period. 6 In addition, a single negativeultrasound test in those with low clinical pretest probability safely excludes DVT. 2

Contrast venography is useful when US results are equivocal or when clinicalprobability is high despite the negative US study. This also holds true for isolatedcalf vein thrombosis which can result in chronic venous insufficiency if untreated. 2

Following spiral CT for suspected PE, CT images of the deep veins can beobtained (indirect CT venography). This is now being used to diagnose both PE

and DVT in the same sitting which simplifies and shortens the work-up. 7 Thesensitivities and specificities of indirect CT venography range from 97% to 100%.8-10 It has the added advantage of demonstrating the IVC and iliac veins.

10Chapter 2 : Clinical Diagnosis


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D-dimer may also be used to limit the need for serial testing in patients withsuspected DVT where a negative test in the low pre-test probability has a negativepredictive value of >99%. 11 A low clinical probability, normal ultrasound andnegative d-dimer virtually rules out DVT. 12 However, in those patients withcancer, recent surgery or elevated bilirubin levels, the negative predictive valueof D-dimer is less. In pregnancy, low levels of D-dimer make VTE unlikely.

Figure 1: Algorithm for diagnosing DVT using clinical assessment,venous ultrasonography and D-dimer testing 13

# Re-evaluate history and review ultrasound for features suggestive of old ratherthan new thrombosis. If ultrasound findings are inconclusive, venography shouldbe considered.*In patients with a high clinical probability or who cannot return for serialultrasonography, venography is recommended.

11

Low Clinical Probability Intermediate or High Clinical Probability

D-dimer test Venous ultrasonography

negative positive negativepositive

exclude DVT

Signs or symptoms of suspected DVT

Clinical Probability

venousultrasonography

diagnose DVT D-dimer test

negative positive # positive negative

excludeDVT

diagnoseDVT serial venous

ultrasonography*

exclude DVT

positive negative

diagnoseDVT

excludeDVT

Chapter 2 : Clinical Diagnosis


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2.2.2 Suspected pulmonary embolismAs with DVT, patients suspected of PE should be stratified into high-,moderate- and low-probability groups (Table 2). Clinical information by itself,however, is inadequate to confirm or exclude the diagnosis of PE.

Patients who are haemodynamically unstable or severely hypoxic should be startedon treatment (see Chapter 4, Fig 3) and further investigations may be needed toconfirm the diagnosis. Spiral CT allows direct visualization of clot within thepulmonary arteries. Pooled analysis 14 using pulmonary angiography has shownspiral CT to have an overall sensitivity & specificity of 72% and 95%respectively. The sensitivity is higher for central PE (94%). Spiral CT can alsobe used to make alternative diagnoses that would explain the symptoms andsigns.

In stable patients with suspected PE, a DVT demonstrated clinically andconfirmed on US support the diagnosis of PE. This can be further confirmed bya ventilation-perfusion (V/Q) scan or a spiral CT. A low level D-dimerconcentration (


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Recurrent symptoms may be due to a variety of non-thrombotic disorders e.g.venous reflux or venous insufficiency/ post-thrombotic syndrome. Up to 70% of patients with non-thrombotic disorders may be incorrectly labelled as havingrecurrent DVT with the unnecessary course of long-term anticoagulant therapy 16

Contrast venography is the gold standard for diagnosis of recurrent DVT.Real-time compression ultrasound is of limited value.



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REFERENCES:

1. Anand S, Wells PS, Hunt D, Brill-Edwards P, Cook D, Ginsberg JS. Does this patient havedeep vein thrombosis? JAMA 1998;279:1094-1096

2. Wells, Hirsch J, Anderson DR, et al. Accuracy of clinical assessments of deep-vein thrombo-sis. Lancet 1995;354:1275-1297

3. Pradoni P, Polistena P, Bernardi E, et al. Upper extremity deep veinthrombosis. Arch Intern Med 1997;157:57-62

4. PS Wells, DR Anderson, J Ginsberg. Assessment of deep vein thrombosis or pulmonaryembolism by the combined use of clinical model and non-invasive test. Seminars in Thrombo-sis and Hemostasis 2002;26:643-656

5. Quinn DA, Fogel RB, Smith CD, et al. D-dimers in the diagnosis of pulmonary embolism. AmJ Resp Crit Care Med 1999;159:1445-1449

6. Cogo A, Lensing AWA, Koopman MWM, et al. Compression ultrasonography for diagnosticmanagement of patients with clinically suspected deep vein thrombosis: Prospective cohort

study. Br Med J 1998;316:17-207. Ciccotosto C, Goodman L, Washington L, Quiroz F. Indirect venography following CT pul-monary angiography: spectrum of CT findings. J Thoracic Imaging 2002;17:18-27

8. Loud PA, Katz Ds, Bruce DA, et al. Deep venous thrombosis with suspected pulmonaryembolism: detection with combined CT venographyand pulmonary angiography. Radiology 2001;219:498-502

9. Gary K, Kemp JL, Wojcik D, et al. Thromboembolic disease. Comparison of combined CTpulmonary angiography and venography with bilateral legsonography in 70 patients. AJR 2000;175:997-1001

10. Coche EE, Hamoir XL, Hammer FD, et al. Using dual-detector helical CT angiography to

detect DVT in patients with suspicion of PE: diagnostic value & additional findings. AJR2001;176:1035-1039

11. Wells PS, Anderson DR, Guy F, et al. Application of a clinical model for the management of hospitalized patients with suspected deep vein thrombosis. Thromb Haemost 1999;81:493-498

12. Perrier A, Desmarias S, Miron MJ, et al. Non-invasive diagnosis of venous thromboembolismin outpatients. Lancet 1999;353:190-195

13. J Hirsh, A Lee. How we diagnose and treat deep vein thrombosis. Blood; 2002 (99): 3102-3110.

14. Forgie MA, Wells PS, Wells G, Millward S. A systematic review of the accuracy of helical CTin the diagnosis of acute pulmonary embolism [Abstract] Blood 1997 ;90:3223

15. Anderson DR, Wells PS. D-dimer for the diagnosis of venous thromboembolism. Curr OpinHaematology 2000:7;286-301

16. Lensing AWA, Prandoni P, Prins HR, Buller HR. Deep vein thrombosis. Lancet 1999;353:479-485

17. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embo-lism. Results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED).

JAMA 1990; 263: 27532759. [Medline Link]



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18. Turkstra F, Kuijer PM, van Beek EJ, Brandjes DP, ten Cate JW, Buller HR.Diagnostic utilityof ultrasonography of leg veins in patients suspected of having pulmonary embolism. AnnIntern Med 1997; 126: 775781. [Fulltext Link] [Medline Link] [BIOSIS Pre-views Link]

19. Meyerovitz MF, Mannting F, Polak JF, Goldhaber SZ. Frequency of pulmonary embolism in

patients with low-probability lung scan and negative lower extremity venous ultrasound.Chest 1999; 115: 980982. [Medline Link] [BIOSIS Previews Link]

20. Lesser BA, Leeper KU Jr, Stein PD, et al. The diagnosis of acute pulmonary embolus inpatients with chronic obstructive pulmonary disease. Chest 1992;102: 1722.[Medline Link]

21. PS Wells, J Ginsberg, DR Anderson. Use of a clinical model for safe management of patientswith suspected pulmonary embolism Ann Intern Med 1998;129:997-1005

22. Cross JJL, Kemp PM, Walsh CG, Flower CD, Dixon AK. A randomized trial of spiral CT and

ventilation perfusion scintigraphy for the diagnosis of pulmonary embolism. Clin Radiol 1998; 53: 177182. [Medline Link]

23. Garg K, Welsh CH, Feyerabend AJ, et al. Pulmonary embolism: diagnosis with spiralCT and ventilation-perfusion scanningcorrelation with pulmonary angiographic resultsor clinical outcome. Radiology 1998; 208:201208. [Medline Link] [BIOSISPreviews Link]

24. Mayo JR, Remy-Jardin M, Muller NL, et al. Pulmonary embolism: prospective comparisonwith spiral CT with ventilation-perfusion scintigraphy. Radiology 1997;205:447-452

25. Harvey RT, Gefter WB, Hrung JM, Langlotz CP. Accuracy of CT angiography versus pulmo-nary angiography in the diagnosis of acute pulmonary embolism:evaluation of the litera-ture with summary ROC curve analysis. Acad Radiol 2000;7: 786797. [MedlineLink]

26. ACCP Consensus Committee on Pulmonary Embolism. Opinions regarding the diagnosis andmanagement of venous thromboembolic disease. Chest 1998; 113:499504.[Medline Link] [BIOSIS Previews Link]

27. Tapson VF, Carroll BA, Davidson BL, Elliott CG, Fedullo PF, Hales CA, et al. The diagnosticapproach to acute venous thromboembolism: clinical practice guideline. American Tho-racic Society. Am J Respir Crit Care Med 1999; 160:10431066. [Medline Link][BIOSIS Previews Link]

28. Elliott CG, Goldhaber SZ, Visani L, DeRosa M. Chest radiographs in acute pulmonaryembolism: results from the International Cooperative Pulmonary Embolism Registry.Chest 2000; 118: 3338. [Medline Link] [BIOSIS Previews Link]

29. Grifoni S, Olivotto I, Cecchini P, et al. Utility of an integrated clinical, echocardiographic, andvenous ultrasonographic approach for triage of patients with suspected pulmonary embo-lism. Am J Cardiol 1998; 82: 12301235. [Medline Link] [BIOSIS PreviewsLink]

30. Perrier A, Tamm C, Unger PF, Lerch R, Sztajzel J. Diagnostic accuracy of Doppler-echocardiography in unselected patients with suspected pulmonary embolism. Int J Cardiol1998; 65: 101109. [Medline Link] [BIOSIS Previews Link]



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31. Miniati M, Monti S, Pratali L, et al. Value of transthoracic echocardiography in the diagnosisof pulmonary embolism: results of a prospective study in unselected patients. Am JMed 2001; 110: 528535. [Fulltext Link] [Medline Link]

32. Harris WH, Salzman EW, Athanasoulis C, et al. Comparison of 125I fibrinogen count scanningwith phlebography for detection of venous thrombi after elective hip surgery. N Engl J Med1975; 292; 665-7

33. Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998; 129;1044-1049

34. Forbes K, Stevenson AJ. The use of power Doppler ultrasound in the diagnosis of isolateddeep venous thrombosis of the calf. Clin Radiol 1998; 53:752-4

35. Borris LC. Comparison of real-time B-mode ultrasonography and bilateral ascendingphlebography for detection of postoperative deep vein thrombosis following elective hipsurgery. The Venous Thrombosis Group. Thromb Haemost 1989; 61; 363-5

36. Ginsberg JS, Wells PS, Kearon C, at al. A rapid whole blood assay for D-dimer markedlysimplifies diagnosis of pulmonary embolism. Ann Intern Med 1998;129:1006-1011

37. Raju S, Owen S, Neglen P. The clinical impact of iliac venous stents in the management of chronic venous insufficiency. J Vascular Surgery 2002;35:8-15

38. Goldhaber SZ. The perils of D-dimer in the medical intensive care unit. Crit Care Med 2000;28; 583-85

39. Janssen MCH, Wollersheim H, Verbruggen B, Novakonva IRO. Rapid D-dimer assays toexclude deep venous thrombosis and pulmonary embolism; current status and newdevelopments. Semin Thromb Hemost 1998;24;393-400.

40. Shah AA, Buckshee N, Yankelevitz DF, et al. Assessment of deep venous thrombosis usingroutine pelvic CT. Am J Roentgenol 1999; 173; 659-63

41. Weinmann EE, Salzman EW. Medical progress: deep vein thrombosis. N Engl J Med 1994;331; 163-4142. Larcom P, Lotke P, Steinberg M, et al. Magnetic resonance venography versus contrast

venography to diagnose thrombosis after joint surgery. Clin Orthop 1996;(331);209-215



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3.1 INTRODUCTION

Deep vein thrombosis (DVT), particularly of the lower limbs, occurs eitherspontaneously or in patients admitted to hospital either for a surgical or medicalproblem. The occurrence of DVT in hospitalised patients is dependent upon variousrisk factors. The reported incidence of DVT varies from 0.45% to 30%. 1 Astudy done in University Hospital Kuala Lumpur reported an incidence of 76.5%in orthopaedic patients undergoing surgery. 2 Up to 50% of patients withasymptomatic DVT may go on to have pulmonary embolism (PE), and in asignificant number of cases, it is fatal.

Hospital patients may be stratified according to VTE risk (Table 1). It isrecommended that all hospital patients at moderate or high risk should receive

specific prophylaxis.

High-risk groups of hospital patients have an incidence of DVT in screeningstudies of 40 - 80%, and an above average risk of fatal PE of 1-10% (Table 1).Effective and safe prophylactic measures against VTE are now available formost high-risk patients. There are two approaches to the prevention of PE:

1. Secondary prevention early detection and prompt treatment of

subclinical venous thrombosis by careful screening of post-operativepatients using a reliable test.

2. Primary prophylaxis the use of drugs or mechanical methods that havebeen proven to be effective in preventing the occurrence of thrombosis.

Primary prophylaxis is naturally preferred in clinical circumstances becauseprevention is more effective than treatment of these thromboembolic complications.

Ideally, the primary prophylactic measure would be effective, safe, easy toadminister, cost effective and would encourage good compliance with the patient,nurses and physicians. Currently, the prophylactic measures that are commonlyused are low dose UFH, LMWH, oral anticoagulants and intermittent pneumaticleg compression.

Prophylactic measures should be started prior to surgery and then continued untilthe patient is fully mobile. There is abundant data from meta-analyses and placebo-

controlled, double-blind, randomised trials that demonstrate either no increase orsmall increases in the absolute rates of major bleeding with the use of low doseunfractionated heparin or LMWH. 5-11

17Chapter 3 : Prophylaxis


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Although wound haematomas are seen more frequently with these agents,avoidance of an anticoagulant cannot generally be justified on these groundsalone. Alternatively, mechanical methods of prophylaxis may be used as they donot have any risk of bleeding and yet have been efficacious in some groups of patients. 5 If spinal or epidural analgesia is used, prophylaxis may be given after 1hour of needle placement for unfractionated heparin and 6-8 hours for lowmolecular weight heparin.

3.2 METHODS OF PROPHYLAXIS FOR MODERATE AND HIGHRISK GROUPS

A) Mechanical methodsThese include graduated elastic compression stocking and intermittent pneumatic

compression devices. They are effective in preventing DVT in moderate-risk surgical patients. However, there were no methodically sound studies that comparedgraduated compression stockings alone with another form of prophylaxis. 1

Graded compression elastic stockings (GCS) reduce the incidence of leg DVTand enhance the protection afforded by low dose heparin. However data on theireffect in proximal DVT and PE is lacking. Further clinical trials are needed toassess the effectiveness of this method in high-risk patients. One small

disadvantage is that some patients cannot effectively wear these stockings dueto unusual limb size or shape.

Mechanical methods may also be combined with pharmacological prophylaxis toincrease efficacy in high-risk patients. Unlike pharmacological prophylaxis, trialsof mechanical methods have not yet been large enough to establish whether ornot they significantly reduce fatal PE. Moreover they have not been evaluated inmedical patients. However, it seems reasonable to extrapolate efficacy from

studies of DVT in surgical patients. As they do not increase the risk of bleeding,mechanical methods may be preferred in patients at increased risk of bleedingfrom pharmacological prophylaxis. Graduated elastic stockings are contraindicatedin severe leg ischaemia.

B) Pharmacological methodsThese include:

Standard unfractionated heparin (usually in low dosage)

Low molecular weight heparins or heparinoids Oral anticoagulants Dextran 70



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(i) Low dose UFH subcutaneously is effective in preventing DVT and PE inmedical patients and in moderate-risk surgical patients. 9 It has less effect onDVT in hip surgery. An international multicentre trial also established the effec-tiveness of low dose UFH in preventing fatal pulmonary embolism, a significantreduction from 0.7% to 0.1%. 12

This therapy is administered subcutaneously in a dose of 5000U every 12 hoursafter the surgery. Meta-analyses have revealed that low dose heparin reducesthe incidence of all DVT and PE.

Low dose UFH is easy to administer and relatively inexpensive, and does notrequire anticoagulant monitoring.

In elective hip surgery, the efficacy of UFH is increased by adjusting the dose,e.g. 3500 IU 8-hourly, starting two days before surgery and adjusting the dose tomaintain the activated partial thromboplastin time (APTT) ratio in the upper normalrange. 1 Such an adjusted dose regimen is, however, more complicated to use thanfixed doses of UFH or LMWH.

(ii) LMWHs and heparinoids are also given subcutaneously for prophylaxis of VTE. They are effective as once-daily injections. Compared to standard heparins,LMWHs are more effective in orthopaedic surgery and slightly more effective ingeneral surgery without increasing the risk of bleeding. 1,7

Randomised clinical trials comparing LMWH (given once or twice daily) withUFH have shown that the former is as effective as, or more effective than thelatter in preventing thrombosis. Recent meta-analyses also revealed similarfindings. 5-11 LMWH is much less likely to produce heparin-inducedthrombocytopaenia and osteoporosis than unfractionated heparin. 13, 14

The advantages of LMWH include its ease of administration using pre-filledsyringes, non-requirement for monitoring and once-daily injection schedule formost of the preparations. Its main disadvantage is that it is porcine-based and socannot be routinely administered to Muslim patients. Despite its relatively highcost, studies have uniformly concluded that broad application of prophylaxis ishighly cost-effective. 15-22


G r a d e A

G r a d e A


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(iii) Oral anticoagulants may sometimes be used as prophylaxis especiallywhen heparin is contraindicated. The advantages are its ease of administration,low cost and safety. The disadvantages are firstly, they require daily monitoringof the international normalised ratio (INR) or the prothrombin time. The

recommended therapeutic range is 2.0 to 2.5 (2.0 to 3.0 in orthopaedic surgery).1

Secondly, if started at a low dose before surgery, they may reduce the risk of bleeding compared to full anticoagulation at the time of surgery.

In view of these shortcomings and the wide availability of other effective options,there is little rationale for this therapy to be used routinely as prophylaxis.

(iv) The pentasaccharide fondaparinux sodium is the first of a new class of

synthetic antithrombotic agents that acts through selective inhibition of factor Xa.Fondaparinux contains no animal sourced components and has been designed tobind selectively to a single target in plasma, antithrombin (ATIII), the mainendogenous inhibitor of blood coagulation. Clinical trials results using fondaparinuxhave been encouraging. In these trials, 2.5 mg of fondaparinux sodium givenonce daily to patients undergoing orthopaedic surgery, starting 6 hours postoperatively, showed a major benefit over LMWH, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant

bleeding.23-26

3.3 DURATION OF PROPHYLAXIS

Specific antithrombotic prophylaxis should be continued for at least 5 days (theminimum duration for prophylaxis in clinical trials) or until hospital discharge if this is earlier than 5 days. In high-risk patients, prophylaxis should be continueduntil illness and immobility have resolved, or until hospital discharge if this is

earlier.

After hospital discharge, increased risk of VTE may continue for several weeksin patients with continuing risk factors (See Table 2, Chapter 1). In such patients,consideration should be given by the doctor to continue prophylaxis afterdischarge, although such practice has not yet been tested in randomised trials. If the hospital team recommends prophylaxis after discharge, they shouldcommunicate with the patient prior to discharge. Separate guidelines should be

prepared for this and other aspects of antithrombotic therapy.


G r a d e A


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3.4 SPECIAL CONSIDERATIONS

Acute stroke with paralysis of lower limbIt is well recognised that the risk of DVT in acute stroke correlates with thedegree of paralysis 27 and is greater in older patients 28 and those with atrialfibrillation. 29 Numerous recommendations locally and abroad have extrapolatedfrom different patient populations and settings in acute stroke patients. A reviewof the available evidence to date confined to stroke patients is described below.

Evidence from randomised controlled trials in acute stroke patients does notsupport the use of Graduated Compression Stockings (GCS) and IntermittentPneumatic Compression (IPC). 30 A large multicentre trial, Clots in Legs or TEDstockings (CLOTS) is ongoing to answer the above question conclusively with alarger number of patients.

There is a risk reduction of 29% in thromboembolism with aspirin followingischaemic stroke. 31 The International Stroke Trial (IST) compared UFH initiatedwithin 48 hours of ischaemic stroke and continued for 2 weeks to no heparin. 32

This treatment regime reduced thromboembolism and recurrent stroke but thiswas offset by an increased risk of haemorrhagic stroke transformation and ex-tracranial haemorrhage. Therefore, routine use of standard heparin such asthromboprophylaxis cannot be recommended.

In the TAIST study, 33 treatment with tinzaparin at high dose (175 anti-Xa IU/kgdaily) within 48 hours of acute ischaemic stroke was superior to aspirin inpreventing VTE but was associated with a higher rate of symptomaticintracranial haemorrhage. More trials are needed before routine use of LMWHcan be recommended.

Graduated compression stockings with or without IPC can be used if otherconcomitant risk factors such as obesity, previous DVT, AF and malignancy arealso present.

Acute spinal cord injury or disease causing lower limb paralysis (e.g.Guillain-Barre syndrome)Intermittent pneumatic compression, with or without subcutaneous LMWH oradjusted dose subcutaneous UFH is recommended. 34-35


G r a d e A

G r a d e B


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Critical ischaemia or amputation of the lower limb Subcutaneous low-dose standard heparin ( 5000 IU, 8 hourly ) Adjusted dose warfarin ( INR 2.0 - 3.0 ) 36

No prevention needed for amputation.

3.5 OBSTETRICS AND GYNAECOLOGY HRT AND VTE

Exogenous oestrogens are associated with an increased risk of VTE. 37

A number of epidemiological case control studies have provided evidence linkingHRT and VTE. 38-41 Women suffering from thrombophilic traits are more at risk of VTE.

There is a paucity of similar epidemiological studies in Malaysia. The incidenceof VTE in Malaysia is probably less than in the Caucasian population.

Routine screening for thrombophilia is not recommended prior to commencing orcontinuing HRT. (42-63) It is recommended that the risk of VTE be discussed withthe patient in the context of overall benefits of HRT and family history of VTE infirst or second degree relatives be obtained. If the above history is positive,selected screening is indicated. The presence of multiple risk factors (Table 2,Chapter 1) may suggest that HRT is best avoided.

In patients whose history is suggestive of VTE but in the absence of objectivetesting, prophylaxis is recommended.

In the absence of underlying thrombophilic defect or in cases of VTE occurringmore than a year earlier, HRT can be prescribed. Transdermal therapy isrecommended in such a situation. The patient should be aware of the potentialfor a venous thrombotic event to develop and the need to report promptly anysuch symptoms. However, HRT is best avoided in patients in whomthrombophilia has been identified.

With regards to patient on HRT undergoing surgery, appropriate assessment of the thrombotic risk should be made. There is no indication to routinely stop HRTprior to surgery provided appropriate thromboprophylaxis, such as low molecularweight heparin or low dose heparin is employed.


G r a d e C


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OCP and VTE (Ref: 64)

The combined OCP is associated with changes in the coagulation system, whichmay be regarded as prothrombotic. These changes correlate with the oestrogencontent but even the low dose preparations are associated with changes in thecoagulation system.

There is a higher risk of VTE in OCP users due to the higher oestrogen contentcompared to HRT. In patients undergoing elective surgery, the decision to stopOCP 4-6 weeks before surgery must be balanced against the risk of unwantedpregnancy. These risks (development of VTE & unwanted pregnancy) must becommunicated to the patient. Effective alternative method of contraception mustbe recommended. Progestogen-only contraceptives are not associated with any

increased risk of VTE and can be used as an alternative.

In the absence of other risk factors, there is insufficient evidence to support apolicy to routinely stop the combined OCP prior to elective surgery. There isinsufficient evidence to support routine thromboprophylaxis in these women with-out additional risk factors.

However in emergency surgery, the risk of VTE is higher. Thromboprophylaxis

is recommended for a patient taking the combined OCP undergoing suchsurgery.

For patients undergoing uncomplicated minor or intermediate procedures (e.g.curettage or laparoscopy) there is no evidence to support stopping the combinedpill or the use of thromboprophylaxis.

Precaution

When HRT and OCPs are given in conjunction with coumarins, care must betaken to avoid potentiation of the anticoagulant effect and more frequentmonitoring of the INR is required. However, concomitant coumarin usage is nota contraindication to HRT or OCP use.

Caesarian SectionCaesarian section increases the risk of thromboembolism by approximately 10-fold. 65 Patients should have their risk stratified to determine what prophylaxis is

needed (table 2).



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Table 2:


Risk Assessment Profile for Thromboembolism in Caesarean Section.

Risk Level

Low risk

Elective caesarian section-uncomplicated pregnancyand no risk factors

Moderate risk - Age >35 years Obesity >80kg. Para 4 or more Gross varicose veins Current infection Preeclampsia Immobility prior to surgery>4 days Major current illness e.g. heart or lung disease, cancer, nephrotic

syndrome

Emergency caesarian section in labour

High risk- A patient with 3 or more moderate risk factors from above Extended major pelvic or abdominal surgery e.g. caesarian

hysterectomy Patients with personal or family history of deep vein

thrombosis; pulmonary embolism or thrombophilia; paralysis of lower limbs

Patients with antiphospholipid antibody

Prophylaxis

Early mobilisation and

hydration

Consider one of a variety of prophylactic measures

heparin / LMWH prophylaxis compression stockings

REFERENCE:1. Wells PS, Lensing AW and Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism: A Meta Analysis. Arch Int Med 1994;67-72.

2. Dhillon KS, Askander A, Doraisamy S. Postoperative deep vein thrombosis in Asian patientsis not a rarity. J Bone Joint Surg (Br) 1996; 78-B: 427-430

3. Gallus AS, Salzman EW, Hirsh J. Prevention of VTE: In: Colman RW, Hirsh J, Marder VJ, eal, eds. Haemostasis and thrombosis: basic principles and clinical practice. 3 rd ed. Philadel-phia, PA: JB Lippincott, 1994: 1331-1345.

4. Nicholaides AN, Bergqvist D, Hull R, et al. Prevention of VTE: international consensusstatement ( guidelines according to scientific evidence). Int Angiol 1997; 16: 3-38.

5. Clagett GP, Reisch JS. Prevention of VTE in general surgical patients: results of a meta-analysis. Ann Surg 1988;208:227-240

6. Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venousthrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopaedic and urologic surgery. N Engl J Med 1988; 318:1162-1173

7. Nurmohamed MT, Roselandaal FR, Buller HR, et al. Low-molecular weight heparin versusstandard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992; 340:152-156

8. Kakkar VV, Cohen AT, Edmonson RA, et al. Low molecular weight versus standard heparinfor prevention of VTE after major abdominal surgery. Lancet 1993; 341:259-2659. Jorgensen LN, Wille-Jorgensen P, Hauch O. Prophylaxis of postoperative thromboembolism

with low molecular weight heparins. Br J Surg 1993; 80:689-704


34/63


10. Koch A, Bouges S, Ziegler S, et al. Low molecular weight heparin and unfractionated heparinin thrombosis prophylaxis after major surgical intervention: update of previous meta-analyses.Br J Surg 1997; 84:750-759

11. Thomas DP. Does low molecular weight heparin cause less bleeding? Thromb Haemost 1997;78:1422-1425

12. Kakkar VV, Corrigan TP, Fossard DP, etal. Prevention of fatal postoperative pulmonary

embolism by low doses of heparin: an international multicentre trail. Lancet 1975; 2: 45-51.13. Hirsh J., Anand SS, Halperin JL, Fuster V., Guide to anticoagulant therapy, Heparin: A

statement for healthcare professionals from the American Heart Association Circulation,2001:103:2994-3016

14. Schulman S. Hellgren Wangdahl, Pregnancy, heparin and osteoporosis, Thromb Haemostat2002:87:180-181

15. Salzman EW, Davies GC. Prophylaxis of VTE: analysis of cost-effectiveness. Ann Surg 1980;191:207-218

16. Hull RD, Hirsh J, Sackett DL, et al. Cost-effectiveness of primary and secondary preventionof fatal pulmonary embolism in high-risk surgical patients. Can Med Assoc J 1982; 127:990-995

17. Oster G, Tuden RL, Colditz GA. Prevention of VTE after general surgery: cost-effectivenessanalysis of alternative approaches to prophylaxis. Am J Med 1987; 82:889-899

18. Oster G, Tuden RL, Colditz GA. A cost-effectiveness analysis of prophylaxis against deep-vein thrombosis in major orthopaedic surgery. JAMA1987; 257:203-208

19. Hauch O, Khattar SC, Jorgensen LN. Cost-benefit analysis of prophylaxis against deep veinthrombosis in surgery. Semin Thromb Hemost 1991; 17(suppl 3):280-283

20. Paiement GD, Wessinger SJ, Harris WH. Cost-effectiveness of prophylaxis in total hipreplacement. Am J Surg1991; 161:519-524

21. Bergqvist D, Matzsch T. Cost/benefit on thrombo-prophylaxis. Haemostasis 1993; 23(suppl1):15-1922. Bergqvist D. Lindgren B, Matzsch T. Comparison of the cost of preventing postoperative

deep vein thrombosis with either unfractionated or low molecular weight heparin. Br J Surg1996; 83:1548-1552

23. Bauer, K.A., Eriksson, B.I., Lassen, M.R., & Turpie, A.G.G., for the Steering Committee of the Pentasaccharide in Major Knee Surgery Study, November 2001, Fondaparinux Comparedwith Enoxaparin for the Prevention of Venous Thrombeombolism after elective Major KneeSurgery, N England J Med, Vol. 345, No.18.

24. Lassen, M.R., Bauer, K.A., Eriksson, B.I., & Turpie, A.G.G., for the European Pentasaccharide

Hip Elective Surgery Study (EPHESUS) Steering Committee, May 2002, Postoperativefondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism inelective hip-replacement surgery: a randomized double-blind comparison, The Lancet, Vol.359, p.1715-20.

25. Eriksson, B.I., Lassen, M.R., Bauer, K.A., & Turpie, A.G.G., for the Steering Committee of the Pentasaccharide Hip-Fracture Surgery Study, November 2001, Fondaparinux comparedwith enoxaparin for the prevention of venous thrombeombolism after hip-fracture surgery, NEngland J Med, Vol. 345, No.18, p.1298-304.

26. Turpie, A.G.G., Bauer, K.A., Eriksson, B.I., & Lassen, M.R., for the PENTATHLON 2000Study Steering Committee, May 2002, Postoperative fondaparinux versus preoperativeenoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: arandomized double-blind trial, The Lancet, Vol. 359, p.1721-26.



35/63


27. Brandstater ME, Roth EJ, Siebens HC. Venous thromboembolism in stroke:literature reviewand implications for clinical practice. Arc Phys Rehabil. 1992;73 S379-S391

28. Mulley GP. Avoidable complications of stroke. J R Coll Physicians Londo . 1982;49:279-28329. Noel P, Gregoire F et. al. Atrial Fibrillation as a Risk Factor for deep vein thrombosis and

pulmonary emboli in stroke patients. Stroke 1991;22:760-76230. Mazzone C, Chiodo Grandi F et. al. Physical Methods for preventing deep venous thrombosis

in stroke Cochrane Database Syst. Rev. 2002;(1):CD00192231. Gubitz G, Sandercock P, Counsell C. Antiplatelet therapy for acute ischaemic stroke (Cochrane

Review). In: The Cochrane Library , issue 4, 2000. Oxford, UK:Update Software.32. International Stroke Trial Collaborative Group. The International Stroke Trial (IST):a

randomized trial of aspirin, subcutaneous heparin, both or neither among 19435 pateint withacute ischaemic stroke. Lancet 1997; 349:1569-1581

33. Bath PM, Lindenstrom E , Boysen G et. al. TAIST:a randomized aspirin controlled trial Lancet 2001 Sep 1;358(9283):702-710

34. Thromboembolic Risk Factors ( THRIFT ) Consensus Group. Risk of and prophylaxis forvenous thromboembolism in hospital patients . BMJ 1992; 305: 567 - 74.

35. European Consensus Statement. Prevention of venous thromboembolism. Intern Angiol 1992;11: 151 9.

36. British Soceity of Haematology. Guidelines on oral anticoagulation; second edition. J ClinPathol 1990;43: 177-83.

37. Carter C. The pill and thrombosis: epidemiological considerations. Baillieres Clin ObstetGynaecol 1997; 11:565-85.

38. Jick H, Derby L E, Myers M W, Vasilakis C, Newton K M. Risk of admission for idiopathicvenous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348:981-3.

39. Daly E, Vessey M P, Hawkins M M, Carson J L, Gough P, Marsh S. Risk of venousthromboembolism in users of hormone replacement therapy. Lancet 1996; 348:977-80.40. Grodstein F, Stampfer M J, Goldhaber S Z, et al. Prospective study of exogenous hormones

and risk of pulmonary embolism in women. Lancet 1996; 348:983-7.41. Gutthann S P, Garcia Rodriguez L A, Castallsague J, Oliart A D. Hormone replacement

therapy and risk of venous thromboembolism : population based case-control study. BMJ1997; 314:796-800.

42. Meade T W, Dyer S, Howarth D J, Imeson J D, Stirling Y. Antithrombin III and procoagulantactivity : sex differences and effects of the menopause. Br J Haematol 1994; 74:77-81.

43. Lowe G D, Rumley A, Woodward M, et al. Epidemiology of coagulation factors, inhibitors

and activation markers : the Third Glasgow MONICA Survey. I. Illustrative reference rangesby age, sex and hormone use. Br J Haematol 1997; 97:775-84.

44. Tait R C, Walker I D, Islam S I, et al. Influence of demographic factors on antithrobmin IIIactivity in a healthy population. Br J Haematol 1993; 84:467-80.

45. Tait R C, Walker I D, Islam S I, et al. Protein C activity in healthy volunteers : influence of age,sex, smoking and oral contraceptives. Thromb Haemostas 1993; 70:281-5.

46. Lindoff C, Peterson F, Lecander I, Martinsson G and Astedt B. Transdermal estrogenreplacement therapy : beneficial effects on hemostatic risk factors for cardiovascular disease.Maturitas 1996; 24:43-50.

47. Anonymous. Effects on haemostasis of hormone replacement therapy with transdermalestradiol and oral sequential medroxyprogesterone acetate: a one year double-blind placebocontrolled study. The Writing Group for the Estradiol Clotting Factors Study. Thromb Haemost1996; 75:476-80.



36/63


48. Lip G Y, Blann A D, Jones A F and Beevers D G. Effects of hormone replacement therapy onhemostatic factors, lipid factors and endothelial function in women undergoing surgicalmenopause: implications for prevention of atherosclerosis. Am Heart J 1997; 134:764-71.

49. Koh K K, Mincemoyer R, Bui M N, et al. Effects of hormone-replacement therapy onfibrinolysis in postmenopausal women. N Engl J Med 1997; 336:683-90.

50. Jick H, Jick S S, Gurewich V, Myers M W and Vasilakis C. Risk of idiopathic cardiovascular

death and nonfatal venous thromboembolism in women using oral contraceptives with differingprostagen components. Lancet 1995; 346:1589-93.

51. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors inpostmenopausal women. PEPI (The Postmenopausal Estrogen/Progestin Interventions Trial)Writing Group. JAMA 1995; 273:199-208.

52. Walker I D. Congenital thrombophilia. Baillieres Clin Obstet Gynaecol 1997; 11:431-45.53. Dahlback B, Hillarp A, Rosen S and Zoller B. Resistance to activated protein C, the FV:Q506

allele and venous thrombosis. Ann Hematol 1996; 72:166-76.54. Zoller B, Holm J and Dahlback B. Resistance to activated protein C due to a factor V gene

mutation: the most common inherited risk factor of thrombosis. Trends Cardiovasc Med1996; 6:45-53.

55. Williamson D, Brown K, Luddington R, Baglin C and Baglin T. Factor V Cambridge: A newmutation (Arg306 > Thr) associated with resistance to activated protein C. Blood 1998;91:1140-44.

56. Poort S R, Rosendall F R, Reitsma P H and Bertina R M. A common genetic variation in the3-untranslated region of the prothrombin gene is associated with elevated plasma prothrombinlevels and an increase in venous thrombosis. Blood 1996; 88:3698-703.

57. Van der Mooren M J, Wouters M G, Blom H J, Schellekens L A, Eskes T K and Rolland R.Hormone replacement therapy may reduce high serum homocysteine in post-menopausal

women. Eur J Clin Invest 1994; 24:733-6.58. Hellgren M, Svensson P J. and Dahlback B. Resistance to activated protein C as a basis forvenous thromboembolism associated with pregnancy and oral contraceptives. Am J ObstetGynecol 1995; 173:210-3.

59. Bertina R M, Koeleman B P, Koster T, et al . Mutation in blood coagulation factor V associationwith resistance to activated protein C. Nature 1994; 369:64-7.

60. Anonymous. Risk of and prophylaxis for venous thromboembolism in hospital patients.Thromboembolic Risk Factors (THRIFT) Consensus Group. BMJ 1992; 305:567-74.

61. Whitehead M and Godfree V. Venous thromboembolism and hormone replacement therapy.Baillieres Clin Obstet Gynaecol 1997; 11:587-99.

62. Greer I A. Practical strategies for hormone replacement therapy and risk of venousthromboembolism. Br J Obstet Gynaecol 1998, 105:376-9.

63. Greer I A. Epidemiology, risk factors and prophylaxis of venous thromboembolism in obstetricsand gynaecology. Baillieres Clin Obstet Gynaecol 1997; 11:403-30.

64. Royal College of O&G. Report of the RCOG Working Party on Prophylaxis againstThromboembolism in Gynaecology and Obstetrics. 1995 Chameleon Press Ltd, London

65. Girling JC, de Swiet M. Thromboembolism in pregnancy: an overview. Curr Opinion inObstet. Cynaecol.1996: 458-463.



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4.1 INTRODUCTION

The aim of treatment of VTE is to reduce morbidity and mortality. This is achievedby optimal therapy to prevent thrombus extension and embolisation. Themainstay of therapy is pharmacological. Adjunct therapies include mechanicaldevices like filters and stents.

4.2 INITIAL TREATMENT OF VTE

In clinically suspected VTE, treatment with UFH or LMWH should be givenuntil the diagnosis is excluded by objective testing. Treatment regimens for DVTand PE are similar because the two conditions are manifestations of the samedisease process. Anticoagulation remains the standard treatment.

4.2.1 Heparin regimens Intravenous unfractionated heparinIntravenous UFH remains the standard treatment in most cases of DVT and PE.The optimal duration of initial iv UFH therapy in patients with VTE is between 5to 7 days. The regimen for the administration of iv UFH is as follows:

1. Baseline APTT, PT, FBC, renal profile, liver function test andthrombophilia screen (if indicated).

2. Initial dose of iv bolus UFH 80 IU/kg followed by maintenance infusionat 18 IU/kg/hr.

3. Check APTT at 6, 12 and 24 hours. The target APTT ratio is 1.5 to 2.5.This must be achieved in the first 24 hours and maintained thereafter.

4. Start warfarin therapy at 5 mg on the first 2 days. Thereafter adjust dailydose according to INR.

5. Check platelet count from day 3 till the end of second week.6. Discontinue heparin once target INR (2.0 - 4.0) is achieved on 2

consecutive days.

To standardize the management of iv UFH, a weight-based normogram is used(Table 1).

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TABLE 1: MANAGEMENT OF IV UFH

The APTT monitoring of UFH is sometimes problematic, particularly in latepregnancy, when an apparent heparin resistance occurs due to increasedfibrinogen and factor VIII, which influence the APTT. This can lead tounnecessary high doses of heparin being used with subsequent haemorrhagicproblems. In these situations, it is useful to determine the anti-Xa level as ameasure of heparin dose (target 0.3-0.7 u/ml). (1) However anti-Xa is notavailable in most hospitals and switching to LMWH is recommended.

Subcutaneous unfractionated heparinSubcutaneous UFH is an effective alternative to intravenous UFH for the initialmanagement of DVT. In a meta-analysis, 12 hourly subcutaneous unfractionatedheparin has been shown to be as effective, and at least as safe as intravenousunfractionated heparin in the initial management of DVT. The regimen for theadministration of subcutaneous, unfractionated heparin includes an initialintravenous bolus of 5000 IU followed by subcutaneous injections of 15,000 to20,000 IU 12 hourly. This is monitored by the APTT with the mid-interval APTTmaintained between 1.5-2.5 times the control. 2

Initial dose

APTT < 35 s (90 s (>3x control)

80 IU/kg bolus, then 18 IU/kg/hr

80 IU/kg bolus, then increaserate by 4 IU/kg/hr

40 IU/kg bolus, then increaseInfusion rate by 2 IU/kg/hr

No change

Decrease infusion rate by 2 IU/kg/hr

Hold infusion for 1 hour, then decreaseInfusion rate by 3 IU/kg/hr

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4.2.2 Low molecular weight heparinLMWH is given subcutaneously and does not require monitoring and is aseffective and at least as safe as UFH in the treatment of DVT and PE. 1

Currently available LMWHs and its recommended doses for the treatment of acute VTE are as shown in Table 2).

TABLE 2: LMWHS AND ITS RECOMMENDED DOSES FOR THETREATMENT OF ACUTE VTE

LMWH recommended

Enoxaparin (Clexane)

Nadroparin (Fraxiparine)

Nadroparin (Fraxiparine Forte)

Tinzaparine (Innohep)

Treatment

1 mg/kg twice daily

0.1 ml/kg twice daily

0.1 ml/kg once daily

175 units/kg once daily

Recommended duration of treatment is 7 to 14 days for patients who willsubsequently be continued on warfarin.

Table 3: META-ANALYSIS COMPARING LMWHS TO UFH INTHE IN-PATIENT VS OUTPATIENT MANAGEMENTOF VENOUS THROMBOEMBOLISM (VTE)

Outcome

Recurrent VTE

Pulmonaryembolism

Major bleeding

Total mortality

In-patient LMWHvs UFH RR(95% CI)

0.80(0.53-1.19)

0.97(0.49-1.94)

0.40(0.21-0.76)

0.63(0.42-0.95)

P value

NS

NS


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LMWH= lowmolecular weight heparin; UFH = unfractionated heparin; RR =relative risk ; CI = confidence interval ; p value = probability; NS = notsignificant.

Monitoring of LMWHs with anti-Xa levels is generally not necessary except inrenal failure, extreme obesity and late pregnancy. Peak anti-Xa activity (3 hourspost-injection) should be measured by a chromogenic substrate assay wherefacilities are available. The target therapeutic range for LMWH is between 0.6to 1.0 units/ml.

4.2.3 Adjunct therapyIn the initial management of DVT, adequate analgesia should be given and theleg elevated. A graduated elastic compression stocking should be applied as soonas the patient can tolerate it and mobilisation encouraged.

A temporary caval filter may be required in patients with recurrent PE despitesatisfactory anticoagulation or in situations where anticoagulation iscontraindicated. Where life-threatening massive PE occurs, cardiorespiratoryresuscitation is usually required and intravenous heparin given. Thrombolytictherapy, percutaneous catheter thrombus fragmentation or surgical embolectomywill be required. This will vary with local expertise.

Where DVT threatens leg viability through venous gangrene, the leg should beelevated, anticoagulation commenced and consideration given to venousthrombectomy or thrombolytic therapy.

4.2.4 ThrombolysisThrombolytic agents used are tissue plasminogen activator (tPA) andstreptokinase. They are indicated in massive PE. The dose for streptokinase is250,000IU iv bolus followed by 100,000IU/hr for 24 hours. The dose for tPA is100mg iv over 2 hours. 1

4.2.5 Pulmonary embolectomyIndications are massive PE with failure of thrombolytic therapy orcontra-indication to thrombolysis.

4.2.6 Thrombolysis and venous thrombectomyThere are ongoing prospective studies of both these treatments to reduce postthrombotic syndrome (PTS) following DVT.

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4.2.7 Endovascular stentsEndovascular stents have been used for residual iliac stenosis and result in relief of obstructive venous symptoms and leg oedema. The patency rates whencombined with thrombolysis is more than 80% immediately and 60% at 5 years. 3,4,5

4.3 MAINTENANCE TREATMENT OF VTE

Following initial heparinisation in patients with VTE, maintenance of anticoagulation with oral anticoagulants is recommended. Duration of oralanticoagulation and target INR are shown in Tables 4 & 5.

Following discharge, patiens should be followed up within a week with a repeatINR. If the INR remains within therapeutic range, the same dose is maintainedand the next follow-up will be 2 weeks later. If the INR still remains withintherapeutic range, then monthly follow-up with INR is advised. More frequentvisits are required if therapeutic INR is not achieved. For details of doseadjustment, refer to algorithm. (Figures 1 and 2)

TABLE 4: DURATION OF THERAPY.

Time

3 to 6 months

= 6 months

12 months to lifetime- first event with canceruntil resolved

Therapy

first event with reversible or time-limited risk factor (Surgery, trauma, immobility, oestrogenuse)

idiopathic VTE, first event

- anticardiolipin antibody- antithrombin deficiency- recurrent event, idiopathic or withthrombophilia

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Do se Alterationfor goa l IN R

2.0-3.0

I N R < 2 . 0 INR 3.1 -3 .5 INR 3.6 -4 .0 INR >4.0

Increase

b y 5 % -1 5 %

Decrease

b y 5% -1 5 %

W ithho ld 1

D o s e

Decreaseb y 10 % -1 5%

W ithho ld 2

Doses

Decreaseb y 1 0% -1 5%

D ose A l tera tionfo r Goa l INR

3.0-4.0

I N R < 3. 0INR 4 .1 - 4.5 INR 4 .6 5 .0 INR > 5 .0

Increaseby 5 % - 15 %

Decreaseby 5 % - 15 %

Withho ld 1Dose

Decreaseb y 10 % - 1 5 %

Withho ld 2Doses

Decreaseb y 10 % - 1 5 %

Figure 2: Warfarin Maintenance Dosing Protocol for Goal INR 3.0-4.0 6

Figure 1: Warfarin Maintenance dosing Protocol for Goal INR 2.0-3.0 6

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4.4 VENOUS THROMBOEMBOLISM IN PATIENTSUNDERGOING SURGERY/ ANAESTHESIA

Elective surgery should be avoided in the first month after an acute episode of venous thromboembolism. There is an estimated risk of recurrent VTE of 40% onstopping anticoagulation in the first month after an acute episode. 7

If major surgery is unavoidable within two weeks after a PE or a proximal DVT,anticoagulation should be stopped and an inferior vena caval filter should beinserted. Intravenous heparin should be recommenced as soon as it is safe.

For patients on warfarin during the first month after a VTE, warfarin should bestopped for 4 days for the INR to fall below 2.0. Pre-operative intravenous

heparin should be administered for 2 days before surgery while the INR issubtherapeutic. If the activated partial thromboplastin time is within the therapeuticrange, stopping continuous heparin therapy six hours before surgery should besufficient for heparin to be cleared before surgery. Post-operative intravenousheparin is indicated and should be started not earlier than 12 hours after majorsurgery or delayed longer if there is evidence of bleeding from the surgical site.Heparin should be restarted without a bolus.

For patients in the second or third month of warfarin therapy for acute VTE,pre-operative intravenous heparin therapy is not justified unless there are additionalrisk factors for recurrent VTE (e.g. hospitalisation for acute illness). Post-operativeintravenous heparin is recommended for such patients until warfarin therapy isresumed and the INR is above 2.0.

Patients who have been receiving warfarin for more than three months since theirlast episode of acute VTE do not need pre-operative heparin. They should receive

post-operative prophylaxis as recommended for patients at high risk for VTE e.g.with LMWH until warfarin therapy is resumed and the INR is above 2.0. It shouldbe combined with mechanical methods of prophylaxis such as graduatedcompression stockings or intermittent pneumatic compression.

4.5 VTE IN PREGNANCY

Treatment:

Evidence for the management of VTE during pregnancy is lacking and, in general,recommendations for the management of VTE during pregnancy are extrapolatedfrom studies in non-pregnant patients.

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Heparin has been widely used for thromboprophylaxis and treatment. Neitherunfractionated standard heparin nor low molecular weight heparin crosses theplacenta and thus there is no risk of foetal haemorrhage or teratogenicity effect.

In women with features consistent with VTE, anticoagulant treatment should beemployed until an objective diagnosis is made (Table 6).

Oral anticoagulant treatment during pregnancy :Oral anticoagulants cross the placenta readily and are associated with a charac-teristic embryopathy in the first trimester, central nervous system abnormalitiesand fetal haemorrhage. 8

Warfarin embryopathy consists of nasal hypoplasia and/or stippled epiphyses andoccurs in approximately 6.4% of patients taking warfarin throughout pregnancy. 8

Maintenance treatment with heparinsDuring pregnancy, adjusted-dose subcutaneous, unfractionated heparin orsubcutaneous LMWH are suitable for maintenance treatment of VTE.

Women with antenatal VTE can be managed with an adjusted-dose regimen of subcutaneous unfractionated heparin or subcutaneous LMWH for the remainderof the pregnancy. 8 - 12

The simplified therapeutic regimen for LMWH is convenient for patients andallows outpatient treatment. Women should be taught to self-inject. They canthen be managed as outpatients until delivery.

Duration of therapy

PeripartumWhen VTE occurs in pregnancy, therapeutic anticoagulation should be continuedfor at least six months.

PostpartumFollowing delivery, treatment should continue for at least 6-12 weeks. Warfarincan be used following delivery. Heparin and LMWHs are not secreted into breastmilk and can be safely given to nursing mothers. 13

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Warfarin can be commenced on the second or third postnatal day. Theinternational normalised ratio (INR) should be checked on day two andsubsequent doses titrated to maintain the INR between 2.0 and 3.0. Backgroundheparin/LMWH treatment should be continued until the INR > 2.0 on twosuccessive days.

TABLE 6: RECOMMENDATIONS FOR ANTICOAGULATION INPREGNANCY

Clinical Condition

DVT/PE beforepregnancy; notcurrently anticoagulated

DVT/PE beforepregnancy; currentlyanticoagulated

New DVT/PE during

pregnancy

Currently anticoagulatedfor other reasons (e.g.,atrial fibrillation, valvereplacement)

Peripartum

UFH 5,000 Usc Q 12 hr

sc UFH/treatmentdoses

IV UFH/treatment

doses for 5-10 days,followed by scUFH/treatmentdoses

sc UFH/treatmentdoses

AlternativeStrategy

LMWH/ preventiondoses

LMWH/ treatmentdoses

LMWH/

treatmentdoses

Postpartum

Warfarin to INR 2-3 for 4-6 wk *

Warfarin to INR 2-3 until full coursecompleted *

(minimum, 4-6 wk)

Warfarin to INR 2-

3 until full coursecompleted *

(minimum, 4-6 wk)

Warfarin toappropriate INRdensity *

DVT = Deep venous thrombosis; LMWH = Low-molecular-weight heparin; PE = Pulmonaryembolism; sc = Sub-cutaneous; UFH = Unfractionated heparin.

* Background heparin/LMWH treatment should be continued until the INR > 2.0 ontwo successive days

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Anticoagulant therapy during labour and delivery

The woman should be advised that once she is established in labour or thinks thatshe is in labour, she should not inject any further heparin.

The dose of heparin should be reduced to its prophylactic dose on the day prior toinduction of labour and continued in this dose during labour (for unfractionatedheparin, this means a dose of 5000 iu given 12 hourly. For LMWH preparations,a once-daily regimen should be adopted using the following doses: nadroparin:0.3ml, enoxaparin: 40 mg).

The treatment dose should be recommenced following delivery. Epiduralanaesthesia can be sited only after discussion with a senior anaesthetist, in keepingwith local anaesthetic protocols.

For delivery by elective Caesarean section, the woman should receive aprophylactic dose of LMWH on the day prior to delivery. On the day of delivery,the morning dose should be omitted and the operation performed that morning.The prophylactic dose of LMWH should be given three hours post-operatively(or four hours after removal of the epidural catheter) and the treatment doserecommenced that evening. There is an increased risk of wound haematomafollowing Caesarean section with both unfractionated heparin and LMWH of around 2%.

In patients receiving therapeutic doses of LMWH, wound drains should beconsidered at Caesarean section and the skin incision should be closed withinterrupted sutures to allow drainage of any haematoma.

Any woman who is considered to be at high risk of haemorrhage, and in whomcontinued heparin treatment is considered essential, should be managedwith intravenous, unfractionated heparin until the risk factors for haemorrhagehave resolved. These risk factors include major antepartum haemorrhage,coagulopathy, progressive wound haematoma, suspected intra-abdominal bleedingand postpartum haemorrhage. Unfractionated heparin has a shorter half-life thanLMWH and its activity is more completely reversed with protamine sulphate. If a woman develops a haemorrhagic problem while on LMWH, the treatmentshould be stopped and expert haematological advice sought.

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Prevention of post-thrombotic syndrome

Post-thrombotic syndrome is a severe disabling sequelae of DVT. It ischaracterized by chronic venous oedema, peripheral vascular insufficiencyassociated with chronic venous ulcers. Graduated elastic compression stockingsshould be worn on the affected leg for two years after the acute event to reducethe risk of post-thrombotic syndrome. A RCT in non-pregnant patients has shownthat such therapy can reduce the incidence of post thrombotic syndrome from23% to 11% over this period. 14

4.6 RECOMMENDATIONS FOR ANTICOAGULATION FORESTABLISHED VTE IN STROKE PATIENTS.

The greatest risk of haemorrhagic transformation in acute ischaemic stroke is inthe first 4 days. 15 From IST 16, where medium and low dose heparin are used,there is an increased risk of haemorrhagic stroke transformation and extracranialhaemorrhage with the regime started within 48 hours and continued for 2 weeks.As VTE is usually diagnosed several days after stroke onset, the greatest risk of haemorrhagic transformation has passed. Based on IST data, it may be safe toanticoagulate towards the end of the 2 nd week. This must be balanced againstrisk from the DVT. The clinical decision to anticoagulate is more urgent if theDVT is a proximal one compared with a distal DVT or if the DVT is propagatingproximally on repeated imaging. LMWH or UFH followed by 3 months of warfarin is the standard practice.

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D ia gn o si s o f V T E c o n f ir m e dby ob jec t ive t e s t ?*

M a ss i ve D V T for P E w i thh a e m o d y n a m ic i n st a b i li t y?

S c h e d u le p a t ie n t fo r f u r t h e r i n v e s t ig a t io nS t a r t h e p a r i n if p r e t e st p r o b a b il it y is h i g h

t e st i ng c a n n o t b e p e rfo rm e d in < 1 2 h .

C o n t ra i n d i c a t io n t oa n t ic o a g u la t io n t h e r ap y ?

H is t o ry o f H IT o r H ITs u s p e c t

CPG Management of Venous Tromboemlism

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